Since its discovery in the early 1980s, O-linked-beta-N-acetylglucosamine (O-GlcNAc),
a single sugar modification on the hydroxyl group of serine or threonine residues,
has changed our views of protein glycosylation. While other forms of protein glycosylation
modify proteins on the cell surface or within luminal compartments of the secretory
machinery, O-GlcNAc modifies myriad nucleocytoplasmic proteins. GlcNAcylated proteins
are involved in transcription, ubiquitination, cell cycle, and stress responses. GlcNAcylation
is similar to protein phosphorylation in terms of stoichiometry, localization and
cycling. To date, only two enzymes are known to regulate GlcNAcylation in mammals:
O-GlcNAc transferase (OGT), which catalyzes the addition of O-GlcNAc, and beta-N-acetylglucosaminidase
(O-GlcNAcase), a neutral hexosaminidase responsible for O-GlcNAc removal. OGT and
O-GlcNAcase are regulated by RNA splicing, by nutrients, and by post-translational
modifications. Their specificities are controlled by many transiently associated targeting
subunits. As methods for detecting O-GlcNAc have improved our understanding of O-GlcNAc's
functions has grown rapidly.
In this review, the functions of GlcNAcylation in regulating cellular processes, its
extensive crosstalk with protein phosphorylation, and regulation of OGT and O-GlcNAcase
will be explored.
GlcNAcylation rivals phosphorylation in terms of its abundance, protein distribution
and its cycling on and off of proteins. GlcNAcylation has extensive crosstalk with
phosphorylation to regulate signaling, transcription and the cytoskeleton in response
to nutrients and stress.
Abnormal crosstalk between GlcNAcylation and phosphorylation underlies dysregulation
in diabetes, including glucose toxicity, and defective GlcNAcylation is involved in
neurodegenerative disease and cancer and most recently in AIDS.
Copyright 2009 Elsevier B.V. All rights reserved.